WO2018036416A1 - Efinaconazole preparation method and crystal form m of efinaconazole - Google Patents

Abstract

An Efinaconazole preparation method, a crystal form M of Efinaconazole, and a crystal form M preparation method. The Efinaconazole preparation method comprises: enabling 4-methylenepiperidine hydrochloride or an acid addition salt thereof and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazole-1-group)methyl] ethylene oxide to undergo a reaction in a solution in the presence of at least one of reagents selected from metal alkoxide M(OR₁)_n, metal halide MY_n or metal oxide M_nO, so as generate Efinaconazole. The reaction formula is as follows. In the preparation method, the reaction is complete, the reaction condition is moderate, the yield rate is high, the selectivity is good, and the Efinaconazole having the purity higher than 99% can be obtained by means of simple processing.

Description

Preparation method of fluconazole and crystal form M thereof Technical field

The invention relates to the technical field of pharmacy, in particular to a preparation method of fluconazole, a novel crystal form M thereof, and a preparation method of the crystal form M.

Background technique

In 1994, Japan Scientific Research Pharmaceutical Co., Ltd. (WO1994026734), the first to publish fluconazole (chemical name: (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylene pipe Patent for compounds of pyridin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol).

The patent also discloses a free 50% KOH solution of 4-methylene piperidine hydrochloride, followed by (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H- 1,2,4-triazol-1-yl)methyl]oxirane is obtained as a solvent in ethanol/water at 85 ° C, and purified by column chromatography to obtain effluentazole product. The route is as follows:

CN103080100A discloses a process for preparing fluconazole which is in the presence of a hydroxide of an alkali metal or alkaline earth metal selected from lithium, sodium, calcium and barium or a hydrate thereof in a reaction solvent. (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]epoxy The alkane is reacted with a 4-methylene piperidic acid addition salt, wherein the reaction solvent may be acetonitrile, 1,2-dimethoxyethane, cyclopentyl methyl ether, isopropanol, 1-butanol or 4 -methyl-2-pentanone.

Among the above two methods, the method reported in the WO1994026734 patent has the disadvantages of low yield, high impurities, and purification by column chromatography. The method reported by CN103080100A, although the raw materials used are Higher yields were obtained with 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, but when the starting material was 4-methylene piperidine hydrochloride, the yield It can only reach about 70%, and it is only the yield that can be obtained when the scale is very small. In addition, in the post-treatment of the patented method, if the column chromatography purification is not performed, the purity of the obtained product can only reach about 95%, and in order to ensure the purity of the product, it is necessary to carry out column purification, which is not conducive to industrial amplification.

Polymorphism is ubiquitous in solids. Efluconazole molecules may also produce different crystal forms with different crystal structures and physical properties. Different crystal forms of the same molecule can be analyzed by X-ray powder diffraction spectrum and differential scanning calorimetry. Spectrum and so on. The discovery of polymorphic forms of pharmaceutically useful compounds provides new opportunities to improve the performance characteristics of pharmaceutical products.

Summary of the invention

It is an object of the present invention to provide a process for the preparation of effluconazole.

Another object of the invention is to provide a new crystalline form of effluentazole.

Another object of the present invention is to provide a process for the preparation of a new crystalline form of effluentazole.

The invention provides a preparation method of efconazole, which has the advantages of easy raw materials, simple process, mild reaction conditions and suitable for industrial production. The method comprises the steps of 4-methylene piperidine or an acid addition salt thereof and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H) -1,2,4-triazol-1-yl)methyl]oxirane in any one selected from the group consisting of metal alkoxides M(OR ₁ ) _n , metal halides MY _n or metal oxides M _n O In the presence of a reagent, it reacts in a solvent to form effluconazole, and the reaction formula is as follows.

among them,

HX is absent or is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, and Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; the HX is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; the HX is most preferably hydrochloric acid;

Y is selected from halogen;

M is selected from any one of an alkali metal or an alkaline earth metal, R _{1 is} selected from an alkyl group having 1 to 5 carbon atoms, and n is 1 or 2;

The metal alkoxide M(OR ₁ ) _{n is} selected from the group consisting of sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, magnesium methoxide, magnesium ethoxide, magnesium n-propoxide, calcium methoxide, calcium ethoxide, sodium t-butoxide, and tert-butyl Lithium alkoxide, magnesium t-butoxide, magnesium isobutoxide or magnesium t-pentoxide, preferably magnesium ethoxide, magnesium n-propoxide, magnesium t-butoxide or magnesium isobutoxide, particularly preferably magnesium ethoxide or magnesium t-butoxide ;

The metal halide MY _{n is} selected from the group consisting of lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium chloride, calcium bromide, barium chloride, barium bromide, preferably lithium bromide. , lithium chloride, magnesium bromide or magnesium chloride, particularly preferred is magnesium chloride;

The metal oxide M _n O is preferably selected from lithium oxide, magnesium oxide, calcium oxide, strontium oxide or barium oxide; more preferred is lithium oxide or magnesium oxide.

According to the process of the invention, the effect is achieved independent of the particular 4-methylene piperidonic acid addition salt. In some embodiments, the 4-methylene piperidine acid addition salt can be selected from 4-methylene piperidine hydrochloride, 4-methylene piperidine hydrobromide or 4-methylene A combination of one or more of a piperidine hydroiodide, but is not limited thereto. The 4-methylene piperidine acid addition salt is preferably 4-methylene piperidine hydrochloride, 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodic acid. More preferably, the salt may be 4-methylene piperidine hydrochloride.

The solvent is selected from the group consisting of acetonitrile, 1,2-dimethoxyethane, cyclopentyl methyl ether, isopropanol, 1-butanol, 4-methyl-2-pentanone or N,N-dimethyl A combination of one or more of the carbachamides; preferably, the solvent is acetonitrile or cyclopentyl methyl ether.

The 4-methylene piperidine or an acid addition salt thereof and the (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1, The molar ratio of 2,4-triazol-1-yl)methyl]oxirane is from about 1:1 to 5:1; preferably, the 4-methylene piperidine or acid addition salt thereof And the (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl] ring The molar ratio of oxyethane to be charged is about 1:1 to 3:1, more preferably about 1:1 to 1.5:1.

A charge molar ratio of the 4-methylene piperidine or an acid addition salt thereof to any one of the metal alkoxides M(OR ₁ ) _n , the metal halide MY _n or the metal oxide M _n O Preferably, the 4-methylene piperidine or an acid addition salt thereof is selected from the group consisting of metal alkoxides M(OR ₁ ) _n , metal halides MY _n or metal oxides molar feed ratio of either reagent M _n O is about 1: 1 to 3: 1; more preferably, said 4-methylene piperidine or an acid addition salt selected from metal alkoxide M ( The charge ratio of any one of OR ₁ ) _n , metal halide MY _n or metal oxide M _n O is about 1:1 to 1.5:1.

The reaction is carried out at a temperature of from 0 ° C to 150 ° C. Preferably, the reaction is carried out at from 20 to 120 ° C. The reaction time is usually from 1 h to 48 h. The reaction can be carried out under any pressure, but it is usually carried out under normal pressure.

After the completion of the reaction, the product system is simply post-treated, and the column is separated without column chromatography to obtain an effluent product having a purity of 99.9% or more.

Specifically, the post-treatment is to concentrate the reaction solution to dryness, dissolve in an organic solvent, wash with water, separate the liquid, and then dry and concentrate to obtain an oily substance, and then crystallize the oil with an alcohol-water mixed solvent to obtain The crude form of effluentazole in solid form can be obtained by repeating the crystallization operation to obtain effluent with a purity of 99.9% or higher. Conazole pure product. The organic solvent is selected from one or more of dichloromethane, ethyl acetate or diethyl ether. The alcohol in the alcohol-water mixed solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol.

The method reported in CN103080100A obtains a higher yield when the raw material used is 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, but when the raw material is 4-methylene When the piperidine hydrochloride is used, the yield can only reach about 70%. By the method of the present invention, when the starting material is 4-methylene piperidine hydrochloride, the yield can reach 80 to 90%. Since the cost of 4-methylene piperidine hydrochloride is significantly lower than that of 4-methylene piperidine hydrobromide and 4-methylene piperidine hydroiodide, the stability is better, the use is convenient, and more Conducive to industrial amplification.

In another aspect, the present invention provides a crystal form M of fluconazole having an X-ray powder diffraction pattern of about 7.7°±0.2° and 15.4°±0.2° at a diffraction angle 2θ. , characteristic peaks at 16.7 ° ± 0.2 ° and 18.9 ° ± 0.2 °;

Preferably, the X-ray powder diffraction pattern of the crystalline form M of the fluconazole is also about 10.0°±0.2°, 12.5°±0.2°, 20.2°±0.2°, 23.2°±0.2° at the diffraction angle 2θ. a characteristic peak at 24.5 ° ± 0.2 °, and 25.3 ° ± 0.2 °; preferably, the crystal form M of the fluconazole has the X-ray powder diffraction pattern shown in Figure 1;

Due to different measurement conditions, the 2θ angle and relative intensity of each peak on the XRPD diffraction pattern may vary. Generally, the 2θ angle change is within ±0.2°, but the range may be slightly exceeded. Those skilled in the art should understand that the relative of diffraction The strength may depend, for example, on the sample preparation or the equipment used.

The differential scanning calorimetry pattern of the crystal form M of the fluconazole has a maximum peak at about 87.83 ± 1 ° C. More preferably, the crystal form M of the fluconazole has a difference as shown in FIG. 2 . A scanning calorimetry map is shown.

The invention also provides a preparation method of the crystal form M of efconazole, the preparation method comprises: dissolving the crude product of efconazole in an alcohol solvent, cooling to -10 to 10 ° C, adding water, and mixing The suspension, the crystal form M of efconazole was isolated from the suspension.

The alcohol solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol; preferably, the alcohol solvent is one of methanol and ethanol. Or a variety.

The weight ratio of the crude product of the fluconazole to the alcohol solvent is about 1 Kg: (0.5 to 5) L, and the weight-to-volume ratio of the crude product of the fluconazole to water is about 1 Kg: (0.5 to 5) L.

The method of separating the crystalline form M of effluentazole from the suspension is a conventional separation method such as filtration or centrifugation of the suspension, preferably filtration. The filter cake obtained after the filtration may also be washed with a washing solvent selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol and tert-amyl alcohol. Preferably, the washing solvent is a mixed solvent having a water to ethanol volume ratio of about 1:1.

The inventors have found that during the preparation of Form M of efconazole, the temperature at which water is added is critical. When the temperature is higher than 10 ° C, the precipitated solid is powdery, which is not conducive to filtration and baking; the temperature is lower than -10 ° C When the solid precipitates too quickly, it is easy to form agglomerated impurities, which is not conducive to purification. The crystal form M prepared by the method of the invention has the advantages of good crystallinity, uniform particles, easy filtration, easy drying and the like.

Beneficial effect

Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

The present invention enables 4-methylene piperidine or its acid addition salt and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2) , 4-triazol-1-yl)methyl]oxirane is carried out in the presence of magnesium tert-butoxide or magnesium chloride, the reaction is complete, the reaction conditions are mild, the selectivity is good, the by-products are small, the yield is high, and the simple After the treatment, an effluconazole product having a purity greater than 99.9% can be obtained; furthermore, according to the method of the invention, the yield of the method of the invention is higher regardless of the form of the 4-methylene piperidic acid addition salt of the raw material. .

DRAWINGS

1 is an X-ray powder diffraction pattern of Form M of efconazole in Example 1;

2 is a differential scanning calorimetry diagram of Form M of effluconazole in Example 1;

3 is a polarizing microscope photograph of a crystal form M of effluconazole in Example 1. FIG.

detailed description

The invention is further illustrated by the following specific examples, without limiting the invention.

The inventors of the present invention have intensively studied 4-methylene piperidine or its acid addition salt and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[( The reaction mechanism of 1H-1,2,4-triazol-1-yl)methyl]oxirane found that the specific magnesium salt has a very prominent catalytic effect on the reaction, and when the magnesium salt is magnesium tert-butoxide When introduced in the form of magnesium chloride, the reaction rate is fast, the reaction is complete, the stereoselectivity is good, and the by-products formed are small. Without column chromatography, a product with a purity higher than 99.9% can be obtained by simple post-treatment.

The synthetic route of the present invention can be expressed as follows:

Wherein HX is absent or is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid , methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid.

The possible mechanism of the above reaction is as follows:

The present invention will be further described in detail below with reference to specific embodiments, but the invention is not limited to the following examples.

The sample data measured by the following instruments: H NMR ⁽¹ H NMR) and C NMR ⁽¹³ C NMR) was measured with Bruker Avance III 300 NMR spectrometer, using TMS as the internal standard, the unit is chemical shift ppm; Mass spectra Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometry; purity analysis using a liquid phase model of Waters 2489; color development using a Precision WFH-203B three-use UV analyzer with wavelengths of 254 nm and 365 nm. All temperatures are expressed in ° C (degrees Celsius), and room temperature or ambient temperature means 20 to 25 ° C.

Differential Thermal Analysis (DSC) Test Method

Test instrument model: DSC Q2000, heating rate: 10 ° C / min, heated from 45 ° C to 200 ° C.

X-ray powder diffraction (XRD) test method

Test instrument model: Bruker D8 advance

Test conditions: voltage is 40kV, current is 40mA, scanning type: two-axis linkage; scanning range: 3° to 40°; scanning step: 0.02°; scanning speed: 0.1 second/step.

The TLC silica gel plate is a HSGF-254 thin-layer chromatography silica gel plate produced by Yantai Chemical Plant. The thickness of the chromatography plate used for thin layer chromatography is 0.2±0.03 mm, dichloromethane, ethyl acetate, methanol, and magnesium tert-butoxide. The reagents such as magnesium ethoxide and anhydrous magnesium chloride are of analytical grade and are provided by Sinopharm Chemical Reagent Co., Ltd. The reagents and solvents used are not specially treated unless otherwise specified.

(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane References, Journal of Organic Chemistry, 2014, 79(7), 3272-3278 and patent document CN103180305A, 4-methylene piperidine hydrochloride, 4-methylene piperidine hydrobromide and 4-methylene The piperidine hydroiodide is prepared by reference to patent documents CN103080100A and CN1125814C.

HPLC determination conditions

Chromatography UV detector: Waters2489

Chromatographic two-phase pump: Waters1525

Column: Agilent Zorbax Eclipse Plus C18 column (4.6*100mm, 3.5μm)

Chromatographic conditions:

Mobile phase A: 0.01 M phosphate buffer solution (1.36 g potassium dihydrogen phosphate and 0.5 mL 1 M potassium hydroxide aqueous solution, diluted with water to 1 L) - methanol (volume ratio 92:8), pH 5.7

Mobile phase B: acetonitrile solution

Injection volume: 20 μL, flow rate: 1.0 mL/min, column temperature: room temperature, detection wavelength: 210 nm.

Example 1

In a 250 mL three-necked flask, a thermometer was placed, and a basic 4-methylenepiperidine (5.8 g, 59.7 mmol), acetonitrile 80 mL was added, and stirred at room temperature, and magnesium t-butoxide (t-BuO) ₂ Mg (10.18 g, 59.7 mmol), stirred at room temperature, and added (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl) Methyl]oxirane (10 g, 39.8 mmol) was protected with nitrogen and refluxed for 24 hours. TLC detection indicated that the reaction was substantially complete. The reaction mixture was concentrated to dryness. The oil was stirred and dissolved in 25 mL of ethanol, cooled to 0 to 10 ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) and dried to give a crude product. The crude product was stirred and dissolved again with 25 mL of ethanol, and cooled to 0 to 10 ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1), and dried at 54 ° C to obtain pure fluconazole crystals (crystal form M), white to off-white solid: 9.7 g. Mole yield: 70%, HPLC purity: 99.9%. The X-ray powder diffraction pattern of the white to off-white solid is shown in Figure 1. The differential scanning calorimetry of the white to off-white solid is shown in Figure 2 and the polarized photo is shown in Figure 3.

_{^{1 H NMR (300MHz, CDCl 3}} ): δ8.00 (s, 1H), 7.75 (s, 1H), 7.51-7.45 (m, 1H), 6.78-6.68 (m, 2H), 5.44 (s, 1H) , 4.82 (dd, J = 18.0, 12.0 Hz, 2H), 4.61 (s, 2H), 2.90-2.86 (m, 1H), 2.69-2.66 (m, 2H), 2.32 (br, 2H), 2.21-2.17 (m, 4H), 0.92 (dd, J = 6.0, 3.0 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 162.6, 158.6, 151.4, 146.0, 144.4, 130.8, 124.7, 111.4, 108.1, 104.1, 77.7, 64.4, 55.9, 52.4, 35.2, 7.6. ESI-MS: m/z C ₁₈ H ₂₂ F ₂ N ₄ O [M+H] ⁺ .

Example 2

In a 250 mL three-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydrochloride (6.4 g, 48 mmol), magnesium tert-butoxide (t-BuO) ₂ Mg (8.6 g, 48 mmol), acetonitrile 80 mL, then added (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane ( 10.2 g, 40 mmol), refluxed for 36 h. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved in 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 20 mL of ethanol, and cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to give an off-white solid: 12.0 g, yield: 86%, HPLC purity: 99.9%.

Example 3

In a 250 mL three-necked flask, equip the thermometer, add 4-methylene piperidine hydrochloride (8 g, 60 mmol), magnesium tert-butoxide (t-BuO) ₂ Mg (10 g, 60 mmol), acetonitrile 80 mL, then add (2R ,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (10.2g , 40 mmol), refluxing for 20 hours, TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved in 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to give an off-white solid: 12.3 g, yield: 89%, HPLC purity: 99.9%.

Example 4

In a 250 mL three-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydrobromide (10.7 g, 60 mmol), magnesium tert-butoxide (t-BuO) ₂ Mg (10 g, 60 mmol), acetonitrile 80 mL, then added (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane ( 10 g, 40 mmol), refluxing for 36 hours, TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved in 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to give an off-white solid 12 g, yield: 86%, HPLC purity: 99.9%.

Example 5

In a 250 mL three-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydroiodide (13.5 g, 60 mmol), magnesium tert-butoxide (t-BuO) ₂ Mg (10 g, 60 mmol), acetonitrile 80 mL, then added (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane ( 10 g, 40 mmol), refluxing for 36 hours, TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved in 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to give an off-white solid 12.1 g, yield: 87%, HPLC purity: 99.9%.

Example 6

In a 10 L four-necked flask, a thermometer was placed, and 4-methylenepiperidine hydrochloride ((639 g, 4.78 mol), magnesium t-butoxide (t-BuO) ₂ Mg (815 g, 4.78 mol), 7 L of acetonitrile, Then (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]epoxy The alkane (1 Kg, 3.98 mol) was refluxed for 36 hours, and the reaction was completed by TLC. The reaction mixture was concentrated to dryness to give crude product. The crude product was dissolved in dichloromethane (10L), washed with The oil was concentrated to dryness to obtain 1.5 Kg of an oil. The oil was dissolved in 2 L of ethanol, and cooled to 5 to 10 ° C in an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes, and filtered. The ethanol-water mixed solvent (v/v=1/1) was washed to obtain a crude product. The crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, and then kept warm and stirred. After 1 hour, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1), and dried at 50 ° C to obtain pure fluconazole crystals, white solid: 1.27 Kg, yield: 91%. , HPLC purity: 99.9%.

Example 7

In a 10 L four-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydrochloride (798 g, 5.97 mol), magnesium t-butoxide (t-BuO) ₂ Mg (1018 g, 5.97 mol), acetonitrile 7 L, then Add (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1 Kg, 3.98 mol), refluxed for 20 hours, and TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals eluted eluted eluted eluted eluted The oil was stirred and dissolved with 2 L of ethanol, and cooled to 5 to 10 ° C with an ice bath. 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, which was stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to obtain pure fluconazole crystals, white solid: 1.28 Kg, yield: 92%, HPLC purity: 99.9%.

Example 8

In a 10 L four-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydrobromide (1065 g, 5.97 mol), magnesium tert-butoxide (t-BuO) ₂ Mg (1018 g, 5.97 mol), acetonitrile 7 L, Then (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]epoxy Alkane (1 Kg, 3.98 mol) was refluxed for 36 hours and TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved with 2 L of ethanol, and cooled to 5 to 10 ° C with an ice bath. 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, which was stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to obtain pure fluconazole crystals, white solid 1.23 Kg, yield: 89%, HPLC purity: 99.9%.

Example 9

In a 10 L four-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydroiodide (1343 g, 5.97 mol), magnesium tert-butoxide (t-BuO) ₂ Mg (1018 g, 5.97 mol), acetonitrile 7 L, Then (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]epoxy Alkane (1 Kg, 3.98 mol) was refluxed for 36 hours and TLC showed the reaction was completed. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved with 2 L of ethanol, and cooled to 5 to 10 ° C with an ice bath. 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to obtain pure fluconazole crystals, white solid 1.18 Kg, yield: 85%, HPLC purity: 99.9%.

Example 10

In a 10 L four-necked flask, a thermometer was placed, 4-methylenepiperidine (580 g, 5.97 mol), 7 L of acetonitrile was added, and anhydrous magnesium chloride (568 g, 5.97 mol) and (2R, 3S) were added thereto under stirring at room temperature. 2-(2,4-Difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1 Kg, 3.98 mol). Under a nitrogen atmosphere, the reaction was refluxed for 24 hours, and TLC detection showed that the reaction was substantially complete. The reaction mixture was concentrated to dryness. EtOAc m. The oil was stirred and dissolved in 2.5 L of ethanol, and cooled to 0 to 10 ° C in an ice bath. 2.5 L of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) and dried to give a crude product. The crude product was stirred and dissolved again with 2.5 L of ethanol, and cooled to 0 to 10 ° C with an ice bath, and 2.5 L of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) and dried to obtain a pure product. Drying at 54 ° C to obtain pure fluconazole crystals, white to off-white solid: 970 g, molar yield: 70%, HPLC purity: 99.9%.

Example 11

In a 10 L four-necked flask, equipped with a thermometer, adding 4-methylene piperidine hydrochloride (636 g, 4.76 mol), magnesium ethoxide (EtO) ₂ Mg (545 g, 4.76 mol), acetonitrile 7 L, and then (2R, 3S)-2-(2,4-Difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1Kg, 3.97 Mol), reflux reaction for 36 hours, TLC showed the reaction was complete. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals The oil was stirred and dissolved with 2 L of ethanol, and cooled to 5 to 10 ° C with an ice bath. 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1) to give a crude material. The crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour. After filtration, the filter cake was washed with 200 mL of an ethanol-water mixed solvent (v/v = 1/1). Drying at 50 ° C to obtain pure fluconazole crystals, white solid: 1.15 Kg, yield: 83%, HPLC purity: 99.9%.

Example 12

(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl] in Example 1 The molar ratio of ethylene oxide, magnesium t-butoxide, and 4-methylene piperidine was adjusted to 1:1.4:1.4, and the amounts were 10 g, 9.50 g, and 5.41 g, respectively, and the reaction was carried out in the same manner as in Example 1. Pure fluconazole crystals were obtained, white to off-white solid: 11.8 g, molar yield: 85%, HPLC purity: 99.9%.

Example 13

The solvent acetonitrile in Example 1 was replaced with 1,2-dimethoxyethane, and the reaction was carried out in the same manner as in Example 1 to obtain pure fluconazole crystals, white to off-white solid: 11.2 g, mol. Yield: 80.5%, HPLC purity: 99.9%.

Example 14

The solvent acetonitrile in Example 1 was replaced with cyclopentyl methyl ether, and the reaction was carried out in the same manner as in Example 1 to obtain pure fluconazole crystals, white to off-white solid: 11.1 g, molar yield: 80% , HPLC purity: 99.9%.

Example 15

(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl] in Example 11 The molar ratio of ethylene oxide, magnesium ethoxide, and 4-methylene piperidine hydrochloride was adjusted to 1:1.5:1.5, and the amounts were 1 kg, 681 g, and 795 g, respectively, and the reaction was carried out in the same manner as in Example 11. Pure fluconazole crystals were obtained, white to off-white solid: 1.12 Kg, molar yield: 80.6%, HPLC purity: 99.9%.

Example 16

The magnesium ethoxide in Example 11 was replaced with magnesium methoxide, and the reaction was carried out in the same manner as in Example 11 to obtain pure fluconazole crystals, white to off-white solid: 1.11 Kg, molar yield: 80%, HPLC purity : 99.9%.

Comparative examples 1 to 4

In a 250 mL three-necked flask, a thermometer was placed, and a basic 4-methylenepiperidine (5.8 g, 59.7 mmol), acetonitrile 80 mL was added, and stirred at room temperature, and magnesium t-butoxide (t-BuO) ₂ Mg (10.18 g, 59.7 mmol), stirred at room temperature, and added (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl) Methyl]oxirane (10 g, 39.8 mmol) was protected with nitrogen and refluxed for 24 hours. TLC detection indicated that the reaction was substantially complete. The reaction mixture was concentrated to dryness. The oil was dissolved by stirring with 25 mL of ethanol, and cooled to X ° C with an ice bath. Then, 25 mL of purified water was gradually added dropwise to precipitate a solid, and the mixture was stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1) and dried to give a crude product. The crude product was stirred and dissolved again with 25 mL of ethanol, and cooled to X ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour. After filtration, the filter cake was washed with 10 mL of an ethanol-water mixed solvent (v/v = 1/1), and dried at 54 ° C to obtain an efconazole solid.

When X is -20 to -10, the fluconazole solid of Comparative Example 1 is obtained;

When X is -10 to -1, the fluconazole solid of Comparative Example 2 is obtained;

When X is 11-15, the fluconazole solid of Comparative Example 3 is obtained;

When X was 16 to 20, the fluconazole solid of Comparative Example 4 was obtained.

The product properties of the efconazole solid obtained at different temperatures are shown in Table 1.

Table 1 Product traits of Comparative Examples 1 to 4 and Example 1 at different dropping temperatures

It can be seen from Table 1 that the temperature of the dropwise addition of water when preparing Form M is very critical. When the temperature is higher than 10 ° C, the precipitated solid is powdery, which is not conducive to filtration and baking; when the temperature is lower than -10 ° C, the solid Precipitation is too fast, and it is easy to form agglomerated impurities, which is not conducive to purification.

The method reported in CN103080100A obtains a higher yield when the raw material used is 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, but when the raw material is 4-methylene When the piperidine hydrochloride is used, the yield can only reach about 70%. The inventors repeated the operation of the patent and found that when the starting material is 4-piperidine hydrochloride, more than 30% of (2R,3S)-2-(2,4-difluorophenyl)-3- is still reacted for more than 24 hours. Methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane remained.

In order to obtain a better industrial application prospect, the inventors of the present invention conducted repeated experiments in which, when magnesium hydroxide or magnesium carbonate was used, most of the raw materials in the reaction system were unreacted. In the presence of a magnesium alkoxide or a magnesium halide, the reaction is complete, the reaction conditions are mild, the selectivity is good, the by-products are small, and the yield is high. Moreover, when a magnesium alkoxide is used as a catalyst, the reaction effect is superior to that of the corresponding lithium alcohol salt.

By the method of the present invention, in the presence of a magnesium alkoxide or a magnesium halide, when the starting material is 4-methylene piperidine hydrochloride, the yield can reach about 90%. In addition, since 4-methylene piperidine hydrochloride is significantly lower in cost than 4-methylene piperidine hydrobromide and 4-methylene piperidine hydroiodide, it is stable and better, and is convenient to use. More Conducive to industrial amplification.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (10)

1. A method for preparing fluconazole, which comprises the steps of 4-methylene piperidine or an acid addition salt thereof and (2R, 3S)-2-(2,4-difluorophenyl)- 3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane is selected from the group consisting of metal alkoxides M(OR ₁ ) _n , metal halides MY _n or In the presence of any one of the metal oxides M _n O, the reaction is carried out in a solvent to form effluconazole, and the reaction formula is as follows.

   

   among them,

   HX is absent or is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, and Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; preferably, the HX is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; more preferably, the HX is hydrochloric acid;

   Y is selected from halogen;

   M is selected from any one of an alkali metal or an alkaline earth metal, and R _{1 is} selected from an alkyl group having 1 to 5 carbon atoms, and n is 1 or 2.
2. The method for preparing fluconazole according to claim 1, wherein the metal alkoxide M(OR ₁ ) _{n is} selected from the group consisting of sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, magnesium methoxide, and magnesium ethoxide. , magnesium n-propoxide, calcium methoxide, calcium ethoxide, sodium t-butoxide, lithium t-butoxide, magnesium t-butoxide, magnesium isobutoxide or magnesium t-pentoxide; preferably, the metal alkoxide M (OR _{1 n is} selected from the group consisting of magnesium ethoxide, magnesium n-propoxide, magnesium t-butoxide or magnesium isobutoxide; more preferably, the metal alkoxide M(OR ₁ ) _n is magnesium ethoxide or magnesium t-butoxide.
3. The method for producing fluconazole according to claim 1, wherein the metal halide MY _{n is} selected from the group consisting of lithium chloride, lithium bromide, lithium iodide, magnesium chloride, magnesium bromide, magnesium iodide, and chlorine. Calcium, calcium bromide, barium chloride or barium bromide; preferably, the metal halide MY _n is lithium bromide, lithium chloride, magnesium bromide or magnesium chloride; more preferably, the metal halide MY _n It is magnesium chloride.
4. The method for producing fluconazole according to claim 1, wherein the solvent is selected from the group consisting of acetonitrile, 1,2-dimethoxyethane, cyclopentyl methyl ether, isopropanol, and 1-butyl A combination of one or more of an alcohol, 4-methyl-2-pentanone or N,N-dimethylformamide; preferably, the solvent is acetonitrile or cyclopentyl methyl ether.
5. A crystal form M of efconazole characterized by an X-ray powder diffraction pattern having a diffraction angle 2θ of about 7.7°±0.2°, 15.4°±0.2°, 16.7°±0.2°, and 18.9°±0.2 There is a characteristic peak at °.
6. The crystal form M of fluconazole according to claim 5, wherein the X-ray powder diffraction pattern is also at a diffraction angle of 2θ of about 10.0°±0.2°, 12.5°±0.2°, and 20.2°±0.2. °, 23.2 ° ± 0.2 °, 24.5 ° ± 0.2 °, and 25.3 ° ± 0.2 ° characteristic peaks.
7. The crystalline form M of efconazole according to claim 5, which has the X-ray powder diffraction pattern shown in Fig. 1.
8. The method for preparing a crystal form M of efconazole according to any one of claims 5 to 7, wherein the preparation method comprises: dissolving a crude product of efconazole in an alcohol solvent, and cooling To -10 to 10 ° C, water was added to obtain a suspension, and the crystal form M of efconazole was isolated from the suspension.
9. The preparation method according to claim 8, wherein the alcohol solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol; preferably The alcohol solvent is one or more of methanol and ethanol.
10. The preparation method according to claim 8, wherein the weight ratio of the crude product of the fluconazole to the alcohol solvent is about 1 kg: (0.5 to 5) L, and the crude product of the fluconazole is The weight-to-volume ratio of water is about 1 Kg: (0.5 to 5) L.

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